Alzheimer?s disease (AD) is most commonly diagnosed subsequent to memory deficits, but co-morbidities include a slew of cognitive and non-cognitive disorders including depression, apathy, and deficits in reward learning. While most work on AD has thus far focused on effects in the cortex and hippocampus, the pathophysiology associated with AD is spread throughout the brain, and many of the secondary symptoms suggest involvement of the midbrain dopaminergic system. A recent major study as well as preliminary data indicate that ventral tegmental area (VTA) dopamine neurons may be particularly affected in mouse models of AD prior to the formation of amyloid plaques and neurofibrillary tangles, suggesting a possible role for this region in the prodromal phase of the disease. This field is currently limited by the lack of information on the structural and functional deficits that develop in single dopamine neurons in the early stages of AD, as well as their relationship with decrements in hedonic and reward learning behavior. The experiments in this administrative supplement will therefore focus on two established mouse models of AD. APP/PS1 mice express a mutated human amyloid precursor protein and a deletion of presenilin 1, while triple transgenic 3xTg-AD mice also express a transgene for a human mutant tau. The hypothesis to be tested is that deficiencies in hedonic state and reward learning can be attributed to specific decrements in ionic conductances and synaptic input to VTA dopamine neurons in mouse models of AD. The general strategy will be to measure deficits in dopamine-mediated behavior (sucrose preference and effort-based reward learning assays) in mutant mice aged 6 and 12 months and non-transgenic controls, followed by electrophysiology of single VTA dopamine neurons, both in brain slices and in vivo. The experiments in Aim 1 will focus on intrinsic calcium and potassium ion channel conductances that affect dopamine neuron firing and have been identified in the literature and preliminary data as possibly being affected in AD. The experiments in Aim 2 will focus on glutamate receptor-mediated synaptic input to VTA dopamine neurons, burst firing parameters, and single neuron morphology (including neuritic branching and soma size). Multiple dependent measures (behavior, physiology, and morphology) will be made from individual mice and explored for correlations. Work associated with the parent R01 award is currently identifying critical decrements in dopamine neuron physiology with normal aging, and age is the leading risk factor for AD. By combining results from the parent grant with those obtained in this supplement we will pinpoint unique aspects of dopaminergic pathology in AD versus normal aging and formulate a follow-up proposal focused on potential therapeutic targets and circuit-level interventions.